Journal
REGULATORY TOXICOLOGY AND PHARMACOLOGY
Volume 92, Issue -, Pages 173-181Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2017.11.012
Keywords
GSH depletion; Transgenic mouse assay; Ethyl acrylate; CAS# 140-88-5; Rodent forestomach tumors; gpt delta mouse; Maximum tolerated dose
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Funding
- Arkema Inc.
- BASF SE
- Dow Chemical Company
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Adverse outcome pathways (AOP) and mode of action (MOA) frameworks help evaluate the toxicity findings of animal studies and their relevance to humans. To effectively use these tools to improve hazard identification and risk assessments for ethyl acrylate (EA), knowledge gaps in metabolism and genotoxicity were identified and addressed. For EA, hypothesized early key events relate to its irritation potential: concentration dependent irritation and cytotoxicity, progressing to regenerative proliferation and forestomach carcinogenicity after repeated oral bolus application in rodents. The current research quantitated glutathione (GSH) depletion to assess a kinetically-derived maximum tolerated dose (MTD) in the target tissue and used this information to conduct an in vivo genotoxicity study using current methods. In the mouse forestomach, gavage doses of EA caused GSH depletion to 47% of control at 20 mg/kg and 28% at 100 mg/kg. Cellular redox changes and histopathology support saturation of metabolism and an MTD of similar to 50 mg/kg. No increases in point mutations or deletions occurred in the stomach or liver following a 28 day treatment of gpt delta transgenic mice at gavage doses up to 50 mg/kg/day. These results provide valuable information for evaluating AOP molecular initiating events or MOA key events for EA and other GSH depleting materials.
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